New benzomorphans (methanobenzazocines) and preparation thereof



United States Patent 3,138,603 NEW BENZOMORPHANS (METHANOBENZAZO- CINES)AND PREPARATION THEREOF Everette L. May, Bethesda, Md., assignor to theUnited States of America as represented by the Secretary of theDepartment of Health, Education, and Welfare No Drawing. Filed Oct. 31,1958, Ser. No. 771,165 12 Claims. (Cl. 260-294.3) (Granted under Title35, US. Code (1952), sec. 266) The present invention relates tobenzomorphans and the preparation thereof, and aims generally to providenew and useful materials and processes in this field. Certain aspects ofthe invention have been disclosed in an article by the applicant and aco-worker in the Journal of Organic Chemistry, 22, 1366, publishedNovember 12, 1957, within one year prior to the filing of the presentapplication, which disclosure is incorporated herein by reference.systematically, these benzomorphans may be termed methanobenzazocines,or more specifically 2,6-methano-3-benzazocines.

Objects of the invention include, severally and interdependently, butare not limited to, the preparation of new benzomorphan derivatives,including derivatives useful as intermediates in the preparation offurther derivatives, and useful in certain instances in theinvestigation of the physiological utility of various moieties andsubstituent groups in such compounds, the provision of new benzomorphanderivatives characterized by new moieties and new combinations ofsubstituent groups therewith, and the provision of such materials asracemates, as separated optical isomers, and as separateddiastereoisomers.

The invention resides in the new processes and products herein set forthand is more particularly pointed out in the appended claims. Certainproducts of this invention have been discovered to show superioranalgesic and tranquilizing powers of a potentially medically usefultype and there is evidence that they may have less addiction potentialand toxicity than presently-used pain-relieving drugs, as well as otheradvantages including possible oral effectiveness.

The new compounds made available by the present invention may berepresented by the following structural formula:

wherein R is a member selected from the group consisting of hydrogen andthe hydroxy, alkoXy and acyloxy radicals; R is a member selected fromthe group consisting of hydrogen, methyl, straight chain alkyl, andaralkyl radicals; R is a member selected from the group consisting ofhydrogen, alkyl, methylene and substituted methylene radicals; and R isa member selected from the group consisting of hydrogen and the alkylradicals-and especially compounds of such formula wherein the alkylportions of the said members contain from 1 to 4 carbon atoms, with thelimitation that when R is hydrogen R is other than hydrogen. In thesystematic terminology, the basic nucleus of these compounds may benamed 1,2,3, 4,5,6-heXahydro-2,6-methano-3-benzazocine; and the newcompounds may be correspondingly named with R designated in the8-position of R R and R designated in the 3,11 and 6-positions of thethus numbered nucleus respectively. Certain of the new compounds havealso been given specific names by the World Health Organization as notedin the Official Gazette of the US. Patent Oflice, vol. 751, page 1,February 2, 1960, namely: (1) the l,2,3,4,5,6-hexahydro-8-hydroxy-3,6,11-trimethyl-2,6 methano 3 benzazocine isgiven the international non-proprietary names metazocinum andmetazocine, and (2) the 1,2, 3,4,5 ,6-hexahydro-8-hydroxy-6, 11-dimethyl-3-phenethyl-2, 6-methano 3 benzazocine the correspondingnames Phenazocinum and Phenazocine.

The new compounds as first isolated are racemic, and optical resolutionof typical ones thereof (IVc and VI) is herein disclosed. As shown insaid copending application, screening and other tests evidence thatvirtually all of the neuropharmacologic activity is due in each instanceto the leVo-antipode, while the dextro isomers show low activity and inone instance (IVc) higher acute toxicity.

The synthesis principally employed for the parent (new) benzomorphansinvolves condensation reaction of a benzyl Grignard reagent, e.g.benzylmagnesium chloride (Ia) or the p-methoxy derivative thereof (lb),with a 3,4- dialkylpyridine alkyl halide, e .g. 3,4-lutidine methiodide,to give dihydro bases (II). The latter are hydrogenated selectively totetrahydro derivatives (III) which upon treatment, as with either 48%hydrobromic acid or phosphoric acid, are cyclized to the benzomorphans(IV), O-demethylation occurring simultaneously in the case of III!) toproduce 2-hydroxy-2,5,9-trimethyl-6,7-benzomorphan (IVc) and adiastereoisomer differing at C, (which diastereoisomer is shown in saidcopending application to be analgesically more potent than the principalracemate) Regarding the principal racemate as the normal series, theanalgesically more potent diasterioisomer (minor racemate) may bedesignated by the term iso. The iso and normal racemates, as shown byExamples 1 and 2 hereinafter, differ in melting points and solubilitiesand are separable by fractional crystallization. The synthesis justdescribed may be applied to produce N-substituted and C- substitutedhomologs of IV by using other 3,4 dialky1pyridine alkiodides as startingmaterials.

In an improved process also herein disclosed, We is converted toN-substituted (alkyl or Z-phenethyl) analogs by protecting the hydroxy,as by substituting for its hydrogen a methyl or acetyl group,N-dealkylating with cyanogen bromide-hydrolysis, acylating the resultingsecondary amines and reducing the amides formed with lithium aluminumhydride. A typical example of this conversion is shown in thepreparation of 2-hydroxy-5,9-dimethyl-2- phenethyl-6,7-benzomorphan(VI).

cite t a 1 H36 R CH3 Benzylmagnesium chloride 3,4-lutidine me thiodideHg dihydro base tetrahydro base2,hydroxy2,5,Q-trimethy1-G,7-benzo1norphan (a) R:H; (b) R=OCHa; (c) R:OH

4) LiAlH 3 is) ms.

(0.) R':OCH:s; (b) R'IOCOCHa Compound IVa,2,5,9-trimethyl-6,7-benzomorphan, has also been prepared by analternative synthesis from the bicyclic ketone methobromide (VII), aknown compound obtained from fi-tetralone, by the scheme outlined below.This alternative synthesis of Na is potentially useful for preparinghomologs of Na and We at the 2,5 and 9 positions, and for theaforementioned disastereoisomer of We.

4) P r01 sis 3 is) a; y

VII

While the reactions used here are standard, the sequence i employed isbelieved to constitute a novel process.

The constitution of the basic benzomorphan molecule (IV) was proved bythe degradation of 2,5,9-trimethyl-6, 7-benzomorphan (IVa) to a knowncompound (1,2-dimethylnaphthalene), a proof strengthened by the factthat IVa was synthesized by totally different sequences as shown above.Furthermore IVa was transformed into IVc via nitration, hydrogenationand the diazotization reaction. The latter (IVc) and the diastereoisomerwere each converted to 7-methoxy-1,2-dimethylnaphthalene.

The foregoing and other aspects, objects, and advantages of theinvention will be evident to those skilled in the art from the followingexamples, in which Examples 1 and 3 illustrate the first synthesis abovedescribed; Example 2 the isolation of the diastereoisomer; Example 4 thesecond or alternative synthesis above described;

Examples 5 and 6 the conversion to new N-alkyl or N- aralkyl analogs;Example 7 the resolution of the principal racemate into the opticalisomers; and Examples 8 and I; 9 the conversion of the separated opticalisomers to new analogs; and it will be understood that these examplesare illustrative and not restrictive of the invention, the scope ofwhich is more particularly pointed out in the appended claims.

EXAMPLE 1 A stirred suspension of 50 g. of 3,4-lutidine methiodide andml. of dry ether was treated during 15-20 minutes with 700 ml. of0.31-0.35 M ethereal p-methoxybenzylmagnesium chloride (I). The mixturewas stirred for an additional 60-90 minutes and poured with vigorousstirring into 250 ml. of ice-water containing 50 g. of ammoniumchloride. After addition of 10-15 ml. of concentrated ammoniumhydroxide, the ether layer was extracted 3-4 times with a total of 250ml. of 2 N hydrochloric acid. The combined extracts were basified withice-ammonium hydroxide and the liberated base was extracted with 250 ml.of ether in 4 portions. The combined extracts were dried over sodiumsulfate and the ether evaporated at the water pump.

The resultant 42-45 g. of oil (Ilb) was dissolved quickly in 200 ml. ofice-cold N HCl and the solution shaken under hydrogen with 8 g. of 5%palladium barium sulfate (carrier). After 10-15 hours 0.8-0.9 molarequivalent of hydrogen had been absorbed and reaction had almost ceased.The mixture was then filtered through Filter-Col and basified withice-cold ammonium hydroxide. The liberated material was shaken intoether (three extractions). The combined dried extracts were distilled,the residue at a bath temperature of 140/0.1-0.5 mm. to give 20-24 g. oftetrahydro base (IIIb).

This tetrahydro base (IIIb), with 175 ml. of 48% hydrobromic acid, waskept at 135-140 for -25 hours. The resultant solution was poured intoice-water and basified with concentrated ammonium hydroxide. Extractionwith 250-300 ml. of chloroform in 3-4 portions followed by drying andevaporation of the chloroform gave an oily residue which crystallized ontrituration with ml. of cold methanol. After 10-20 hours at 5 the yieldof 2-hydroxy-2,5,9-trimethyl-6,7-benzomorphan (lVc) was 10-12.5 g.; M.P.228-233". The analytical sample melted at 233-236 while thehydrochloride salt (monohydrated) melted at 194-196.

EXAMPLE 2 Distillation of the methanol from the filtrates of two 50-g.runs of Example 1 left a residue which was distilled at a bathtemperature of 175-200 (0.5 mm.). Fractional crystallization of thedistillate from methanol and acetone gave ultimately 0.8 g. of thehydrochloride of a diastereoisomer of lVc, M.P. 269-271". The basemelted at 215-217 EXAMPLE 3 To a stirred suspension of 12 g. of3.4-lutidine methiodide and 100ml. of dry ether (cooled in ice-water)was added during 5 minutes, 100 ml. of 0.5 M ethereal benzylmagnesiumchloride (1). The mixture was stirred without cooling for 1.5 hours andthe dihydro base (IIa) isolated as described above, then evaporativelydistilled at a bath temperature of 125 (0.5 mm.).

The distillate (5.8 g.) was hydrogenated as described above to give 3.8g. of distilled tetrahydro base (IIIa).

The tetrahydro base (111a) and 38 g. of 85% phosphoric acid were kept at145-150 for 2.5 days, cooled, poured into ice and made alkaline withammonium hydroxide. The resultant oil was dried in ether and distilled(125/ 0.5 mm.) to give 3.3 g. of oil which was dissolved in 50 ml. ofethylacetate and acidified to Congo Red with gaseous hydrogen chloride.On seeding (seed obtained by manipulations with solvents, drying,scratching, etc., of an aliquot part) 2.5 g. of2,5,9-trimethyl-6,7-benzemorphan hydrochloride (IVa), M.P. 167-170,eventually separated. The picrate melted at 122-123 then at 114-115after a recrystallization from alcohol.

EXAMPLE 4 To 11.2 g. of 2,5-dimethyl-9-oxo-6,7-benzomorphan methobromide(VII) was added 170 ml. (5 molar equivalents) of 1.0 M etherealmethylmagnesium bromide. The ether was distilled until the liquid adductbecame much more fluid. The magma was then manually manipulated with astirring rod until all solid passed into the fluid state. The mixturewas decomposed with water and the solids were dissolved in ml. of 6 Nhydrochloric acid. Excess aqueous potassium iodide was added with theformation of the crystalline methiodide. Purified from alcohol it meltedat 247-249; yield 9.4 g.

A distilling flask containing 5.9 g. of this methiodide was kept in asalt bath at 275-280" under a pressure of 0.1-0.4 mm. The soliddecomposed to an oil (tertiary alcohol) which distilled in a yield of3.6 g., B.P. 112-115/ 0.5 mm. This tertiary alcohol, 7 ml. of aceticanhydride and 0.7 ml. of pyridine were refluxed for 3 hours. Excessreagent was removed at reduced pressure and the product was distilled atca. 122/ 0.1 mm. (M.P. of perchlorate, from alcohol, 265-267).

The distillate (2.8 g.) in a distilling flask, immersed in a salt bathat 325-340", lost acetic acid during 30 minutes. The pressure was thenreduced to 0.2 mm. with distillation 6 of the product at -110 yieldingthe 9-methylene derivative. Dissolved in ether, this derivative wasconverted to the crystalline perchlorate with 60% perchloric acid,giving 1.2 g. of crude perchlorate, M.P. 204-219".

This perchlorate (0.3 g.) in alcohol with platinum oxide absorbed onemolar equivalent of hydrogen. The filtered solution gave 0.2 g. of aperchlorate of M.P. 201-210. It was converted to the base (alkali-ether)which in acetone gave a methiodide, M.P. 225-226.5, after arecrystallization from alcohol-ethyl acetate, identical in every respectto the methiodide prepared from the 2,5,9-tri-. methyl-6,7-benzomorphan(IVc) synthesized as described in Example 3.

EXAMPLE 5 A mixture of 1.5 g. of 2-hydroxy-2,5,9-trimethyl-6,7-benzomorphan (We), 15 ml. of methanol and 25 ml. of 3% etherealdiazomethane were magnetically stirred for 4-5 hours. Another 25-ml.portion of the ethereal diazomethane was then added and the clear,yellow solution left at 25 for 3 days. Evaporation of solvents atreduced pressure and evaporative distillation of the residue at /1 mm.gave 1.4 g. of methyl ether (Va) (M.P. of hydrobromide 233-235 This basein 12 ml. of chloroform was added (stirring) during one hour to 0.7 g.of cyanogen bromide in 5 ml. of chloroform. The solution was refluxedfor 3 hours and evaporated to dryness in vacuo. To the residue was added30 ml. of 6%hydrochloric acid and the mixture was refluxed 10-15 hours.After cooling and making alkaline with ammonium hydroxide, the base wasshaken into chloroform. Drying and evaporation of the chloroform left1.3 g. of oil.

This oil, 20 ml. of methanol, 7 ml. of water and 0.8 g. of potassiumcarbonate were stirred and treated during 10 minutes with 1.0 ml. ofphenylacetyl chloride. The mixture was stirred 2-3 hours, diluted to 100ml. with water and extracted thrice with ether. The combined etherextracts were washed With dilute hydrochloric acid, then water, driedand evaporated leaving 1.8 g. of crude amide.

This crude amide was dissolved in 10 ml. of dry ether and treatedgradually with 17 ml. of 1.5 M ethereal lithium aluminum hydride. Themixture was refluxed overnight, decomposed carefully with 5-8 ml. ofwater and filtered. The dried ether filtrate was evaporated to drynessleaving 1.8 g. of crude base which in acetone-ether was converted to 1.2g. of 2'-methoxy-5,9-dimethyl-2-phenethyl-6,7-benzomorphan hydrobromidewith 33% hydrogen bromide in acetic acid; M.P. 242-244.

This hydrobromide (1.3 g.) and 10 ml. of 48% hydrobromic acid wererefluxed vigorously for 20 minutes, cooled in ice and decanted. Theresidue was dried at 60 in vacuo, dissolved in 4 ml. of acetone and thesolution evaporated to dryness. The residue crystallized from 4 ml. ofacetone. After 24 hours at 5 the yield of 2'- hydroxy 5,9 dimethyl 2phenethyl 6,7 benzomorphan (VI) hydrobromide was 1.0 g.; M.P. -168. Thefree base (from methanol-aqueous ammonia) melted at 180-181.

EXAMPLE 6 2-hydroxy-2,5,9-trimethyl-6,7-benzomorphan (IVc, 10 g.) and 10ml. of acetic anhydride were kept on the steam bath for 30-45 minutes,cooled and poured into ice water. After 5 minutes the mixture was madealkaline (while keeping ice-cold) with 50% potassium hydroxide solution.The freed base was quickly shaken-into ether and dried over sodiumsulfate. Evaporation of the ether left 11.5 g. of O-acetyl derivativewhich was converted to 8.8 g. of crude2'-hydroxy-5,9-dimethyl-6,7-benzomor- 7 phan by cyanogen bromidetreatment and acid hydrolysis as described in Example except that 2:1butanol-benzene was used as the extraction solvent.

This 8.8 g. of secondary amine, 100 ml. of methanol, 15-20 ml. of waterand g. of potassium carbonate were stirred and treated during minuteswith 10 ml. of phenylacetyl chloride. After an additional 3 hours, 300ml. of water was added and the mixture was extracted thrice withbutanol-benzene. The combined extracts were washed with dilutehydrochloric acid, then water, dried and taken to dryness in vacuo.

The residue (12 g.) and 100 ml. of dry ether were stirred while addingdropwise 60 ml. of 1.5 M ethereal lithium aluminum hydride. The mixturewas refluxed overnight, cooled in ice and treated carefully with 60 ml.of 48% hydrobromic acid. Addition of an equal volume of water,filtration, washing with cold water then ether, and drying theprecipitate gave 10.5-12 g. of crude hydrobromide of VI whichcrystallized from 11 ml. of acetone and 10 ml. of ethyl acetate in ayield of 7 g., M.P. 166 1703 EXAMPLE 7 A mixture of 4.4 g. of thehydrochloride salt of 2'-hydroxy-2,5,9-trimethyl-6,7-benzomorphan (IVc),5.0 g. of the ammonium salt of (+)-a-bromocamphor-II-sulfonic and 35 ml.of water were warmed to solution, and kept warm until crystals beganseparating. After 2 hours at and 3 hours at 5 the yield of precipitate,M.P. 225- 270, was 6.3 g. This precipitate was dissolved in 200 ml. ofboiling water, and this solution was concentrated to 150 ml. and cooledat 5 overnight to give 3.8 g. of sulfonate salt, M.P. 285288 (dec.).This in 150 ml. of the hot water gave, with addition of ammoniumhydroxide, 1.5 g. of ()-2-hydroxy-2,5,9-trimethyl-6,7-benzomorphan, M.P.182-184. The analytical sample (from aqueous alcohol) had M.P. 183-184.5and [a] 84.4 (c. 0.92, abs. alcohol). The hydrobromide salt crystallizedfrom alcohol-ether; M.P. 238241 [a] -52.0 (c. 2.00, water).

Ammonium hydroxide addition to the combined aqueous filtrates above gave1.7 g. of a mixture of (i)- and (+)-bases which, by fractionalcrystallization from aqueous alcohol, gave 0.36 g. of (:)-IVc and 1.1 g.of 2 hydroxy 2,5,9 trimethyl 6,7 benzomorphan, M.P. 181183. Theanalytical sample melted at 183l84.5; {(11 +84.3 (c. 0.83, abs.alcohol), hydrobromide salt, M.P. 283-242 [a] +52.1 (c. 1.46, water).

EXAMPLES 8 AND 9 By the procedures described in Example 5, the levoanddextro-isomers corresponding to2'-hydroxy-2,5,9-trimethyl-6,7-benzomorphan (We) (see Example 7) wereconverted respectively to the (-)-2'-hydroxy-5,9-dimethyl-2-phenethyl-6,7-benzomorphan (VI) hydrobromide, M.P. 284287, [u] 84.1 (c.0.82, ethanol) and to the (+)-VI hydrobromide, M.P. 284-287", [lX]D+84.4 (c. 1.47, 95% ethanol). The (:)-V1 (base) melted at 159-159.5 andhad [od -121.6 (c. 0.74, 95% ethanol) and the (-)-VI (base) melted at159- 160"; [a] (c. 0.60, 95% methanol).

It is clear from the above examples that a wide variety of O-, N- andC-substituted analogs of We are made available by the present inventionwhich are useful as intermediates and certain of which, have been shownto have useful medical properties particularly of a neuropharmacologicnature, by animal and clinical tests as follows:

The benzomorphans forming the subject matter of the present inventionwhich have been evaluated by the animal tests include thosecorresponding to the Formula VIII:

wherein R is a member selected from the group consisting of hydrogen,hydroxy and methoxy and R is a member selected from the group consistingof methyl and phenethyl, R being methyl when R is other than hydroxyl.Similar evaluation by animal screening of compounds according to theabove formula wherein R is hydroxyl and R is hydrogen or a C -C straightchain alkyl, have shown such to be inactive at sub-toxic doses.

The benzomorphans which have been evaluated clinically at the time ofthe filing of the present application are limited to the phenethylspecies of the above group (Formula VIII: R=OH, R =CH CH Ph).

The benzomorphans corresponding to the above general formula arepreferably administered in the form of their salts with acids such astartaric, citric, acetic, sulfuric, phosphoric, the halogen acids, etc.;the hydrobromide and hydrochloride salts being especially suitable. Itis considered that the acids used to form salts of the drugs in questiondo not alter the pharmacological behavior of the drugs and in effect arerelatively inert substituents which merely alter the solubility of thedrugs, and unqualified reference to the benzomorphans per se, in theappended claims, is to be considered to apply thereto in salt form aswell as in the form of the free base. It will be understood, of course,that the extent by which the weight of the base is increased by theformation of the salt, requires a corresponding increase in the amountof material needed to produce a given neuropharmacological efiect.

The animal screening tests have been conducted on the racemic forms ofall the foregoing benzomorphans (VIII) and on the pure levoanddextro-isomers, where R is OH and R is either CH or CH CH Ph. The mostpracticable synthesis for these benzomorphans produces one racematepredominantly and a diastereoisomer (about C in very low yield; bothhave been tested in animals.

In the mouse screening tests (see below) the analgesic activity (ED andacute toxicity (LD have been determined in accordance with J. Pharmacol.& Exptl. Therap., 107, 385 (1953), and are expressed in mg. of drug perkg. of mouse (subcutaneous administration unless otherwise specified).Morphine sulfate, codeine hydrochloride, and the most popular syntheticanalgesic, meperidine hydrochloride (standard drugs for comparison)have, respectively, ED 2.1, 14.2 and 9.9; and LD 576, 270 and whenevaluated in this Way. Occasionally, in the examples to follow, acompounds ability to block a conditioned response in mice and rats willbe compared with that of the well-known tranquilizing drugchlorpromazine[2-chloro-3-(dimethylaminopropyl)phenothiazine]hydrochloride.

The foregoing and other aspects and advantages of the present inventionwill be evident to those skilled in the art from the following examplesof Table A in which Examples 1 and 2 refer to animal screening tests foranalgesia and acute toxicity; Examples 3-5 refer to animal screeningtests for the above factors and conditionedresponse-blocking action;Examples 68 (similar to 3-5) employ different derivatives; Example 9refers to animal screening for analgesia and acute toxicity of the minorracemate; and Examples 10-32 refer to clinical tests for analgesia,toxicity, and addictiveness of the phenethyl species of the predominantracemate. For convenience of reference, the data for these severalexamples is here summarized in Table A:

Table A [Summary of examples of Neuropharmacologieal Activity, etc., of2-(R)-5,9-dimethyl-2- (R )-6,7-benzomorphans.

Com- Examples, and form Comment R R pound Code No.

NIH :i: Dso au Animal Screenings-Predom. Racemate and Optical Isomersthereof -H OHa 7389 1 CH CH3 7550 2 OH CH 4 7410 3 7571 4 7569 OHCHzCHzPh B 7519 6 7614 7 7613 Animal Screening-Minor Racemate OH -OH37601 9 0.44 70 Clinical Testing-Predominant Racemate OH --CHzCHzPh 751910-19 See Text 7519 See Text 7519 21-32 See Text 1 Oral 23.9. 2 Oral6.4.

B Administered in inert carrier (see text following Example 22) 4 Thiscompound has been designated by the international nonproprietary nameMetazocine, see 751 0.6. 1

6 This compound has been designated by the international nonproprietaryname Phonezocine, see 751 O.G. 1

Table A.Examples 1 and 2 The predominant racemate of(:)-2,5,9-trimethyl-6,7-

benzomorphan (I, R=H, R =CH hydrochloride tested for analgesia by thehot-plate procedure (a modification of the Woolfe MacDonald method) hadan ED of 27.3; LD 155. The 2-methoxy analog (I, R=CH O, R =CH had ED 9.8(no toxicity data available). Thus the latter is somewhat more potentthan codeine, equivalent to merperidine.

Table A .-Examples 3, 4 and 5 dextro-rotatory isomer was analgesicallyinert at a convulsant dose of 20 mg. of the hydrobromide salt per kg.while the levo form had ED 1.7, LD 400. Its thereapeutic ratio issuperior to that of morphine sulfate.

Table A.--Examples 6, 7 and 8 As described above the ED and LD of theprincipal racemate of ;)2-hydroxy-5,9-dimethyl-2-phenethyl-6,7-benzomorphan-hydrochloride Table A.Example 9 The minor diastereoisomerof (i)-2'-hydroxy-2,5,9- trimethyl-6,7-benzomorphan, as hydrochloridesalt, (I, R=CH, R =CH differing from the predominant isomerconfiguratively at C has ED 0.44, LD 70, is therefore 7 times morepotent than the predominant racemate (see Example 3) and nearly 5 timesas active as morphine sulfate.

Table A .Examples 10-19 The hydrobromide salt of the (i)- (I, R=CH, R CHCH Ph) was administered parenterally to a moderate number ofpostoperative patients (original group of ten, confirmed in others).Satisfactory relief of pain was observed in doses of l/ 10 the optimaldose of morphine sulfate 0.6 mg. equivalent to 6.0 mg. of morphinesulfate intravenously). There appeared to be less respiratory depressionthan is caused by an equally analgesic dose of morphine sulfate.

Table A.-Example 20 In one other case of severe root pain not relievedsatisfactorily by other potent analgesics including morphine sulfate, 2mg. of the hydrobromide of this (i )-I (R=CH, R =CH CH Ph) administeredevery 3 hours gave excellent relief of this otherwise intractable pain.After approximately 2 weeks this patient apparently developed notolerance, and no abstinence symptoms were evident.

Table A.-Example 21-32 (Lexington Addiction Studies) The hydrobromidesalt of )-I (R=0H, R CH CH Ph) was administered subcutaneously to formermorphine addicts. On the basis of graded single doses, effects likethose of 20 mg. of morphine sulfate were obtained with a dose of 4 mg.(10 cases). Two subjects (one on a double-blind basis) recevied the drugfour times a day for 21 days. The dose could be increased only to 36 mg.per day, whereas in the same time morphine sulfate dosage can beincreased easily to 250 mg. per day. On abrupt withdrawal, abstinencesymptoms were very mild in both patients compared with the severesyndrome noted on morphine withdrawal after a like period ofadministration. These results are consistent with the aforementionedfindings in the monkey. There were no untoward toxic etfects evident inany of the clinical experiences with this drug (Examples -32).

The above summarized data indicate that ()-I R=OH, R =CH of thepredominant racemate series and the (:)-diastereoisomer (lesserracemate) are promising candidates for clinical use. It is also evidentthat (:)-I (R=OH, R =CH CH Ph) shows superior analgesic andtranquilizing action in animals and man with minimal deleteriousside-actions including low addiction liability compared topresently-used, efficacious analgesic agents. It is possible that thiscompound and one or more of the others described above will also provesuitable for oral administration.

The drug as administered preferably comprises a suitable carrier for thebenzomorphan. Thus for parenteral administration an aqueous solution ofthe benzomorphan in salt form may be employed, preferably buffered, aswith sodium citrate, or the benzomorphan may be dissolved in propyleneglycol and be then diluted with water or buffered aqueous solution tocontain the desired dosage in a standard volume (say in cc. of thesolution). Preferably in the latter case the ultimate carrier solutioncomprises about propylene glycol. In the above examples the drugcomprised carrier as follows: Examples 1-5 and 9, aqueous; Examples 6-8,and 21-32 aqueous/pyropylene glycol about 75/23; Examples 10-20 aqueous,buffered with sodium citrate. The oral administration tests (in Examples3 and 6) for convenience were made with the same solution employed inthe subcutaneous tests in those examples, but obviously other knowninert carriers for phamaceuticals, e.g. milk sugar, suspending fluids,etc., may be appropriately substituted for those employed, and theinvention is not limited to any particular carrier.

It is to be understood that in the following claims, merely for the sakeof brevity, the new compounds are defined in terms of the base, and thatthe claims are to be construed as covering not only the base compoundsbut also the salts of such compounds (e.g. the salts formed thereby withorganic and inorganic acids, alkyl halides, etc.). It is further to beunderstood that because of nomenclature difliculties, when methylene isreferred to in the following claims, such term is to be construed asincluding a single CH group double bonded to C whether or not said groupis further substituted.

The invention described herein, if patented, may be manufactured andused by or for the Government of the United States for governmentalpurposes without the payment to me of any royalty thereon in accordancewith the provisions of the Patent Act of 1952 U.S.C. Sec. 266).

I claim:

1. A chemical compound of the class consisting of a free base and itsnontoxic acid addition salts, the free 12 base being aniso-2-hydroxy-5,9-dimethyl-2-substituted- 6,7-benzomorphan of thefollowing formula:

in which R is a member selected from the group consisting of hydrogen,methyl and phenylalkyl, said alkyl having from 1 to 4 carbons.

2. Iso 2' hydroxy-5,9-dimethyl-2-(fl-phenethyl)-6,7- benzmorphan.

3. Iso-2-hydroxy-5,9-dimethyl-6,7-benzmorphan.

4. Iso 2 hydroxy-5,9-dimethyl-2-(fi-phenethyl)-6,7- benzmorphanhydrobromide.

5. Iso-2-hydroxy-2,5,9-trimethyl-6,7-benzmorphan hydrochloride.

6. Iso-2-acetoxy-2,5,9-trimethyl-6,7-benzmorphan.

7. A chemical compound of the class consisting of a free base and itsnontoxic acid addition salts, the free base being a2'-hydroxy-5,9-dimethyl-2-substituted-6,7-

i benzmorphan of the following formula:

References Cited in the file of this patent UNITED STATES PATENTS Gordonet a1. Feb. 9, 1960 Gordon et a1 Nov. 8, 1960 OTHER REFERENCES May etal.: J. Org. Chem., vol. 20, pp. 257-263, Feb. 1955.

May et al: I. Organic Chem., vol. 22, pp. 1366-1369, Nov. 1957.

May et al.: J. Organic Chem., vol. 21, pp. 899-901,

Eddy et al.: I. Organic Chem., vol. 22, pp. 1370-1372, Nov. 1957.

Eddy et al.: J. Organic Chem., vol. 24, p. 294 1959).

Grewe et al.: Chemische Berichte, p. 279-286 (1948).

1. A CHEMICAL COMPOUND OF THE CLASS CONSISTING OF A FREE BASE AND ITSNONTOXIC ACID ADDITION SALTS, THE FREE BASE BEING ANISO-2''-HYDROXY-5,9-DIMETHYL-2-SUBSTITUTED6,7-BENZOMORPHAN OF THEFOLLOWING FORMULA:
 7. A CHEMICAL COMPOUND OF THE CLASS CONSISTING OF AFREE BASE AND ITS NONTOXIC ACID ADDITION SALTS, THE FREE BASE BEING A2''-HYDROXY-5,9-DIMETHYL-2-SUBSTITUTED-6,7BENZMORPHAN OF THE FOLLOWINGFORMULA: